Tissue-to-plasma ratio

The kidneys and the liver primarily take up phosphorothioated AS-ODN after parenteral administration, accumulating more than 10% each, while the rest of the organs all accumulate less than 1% of the injected dose [110,111,114,116]. It is noteworthy that renal AS-ODN tissue levels exceed that of any other organ [110,113,114], as confirmed by the tissue to plasma ratios of approximately 85 and 20 for kidney and liver, respectively [113,118]. 

In general, the macrolides are administered orally but sometimes also paren-terally. All the members of this group are well absorbed and are distributed extensively in tissues, especially in the lungs, liver, and kidneys, with high tissue to plasma ratios. They are retained in the tissues for long periods after the levels in the blood have ceased to be detectable. Elimination of all macrolides occurs primarily through hepatic metabolism, which accounts for approximately 60% of an administered intravenous dose the remainder is excreted in active form in the urine and bile. With oral and intramuscular administration, urinary excretion decreases, but biliary excretion and hepatic metabolism increase proportionally. Milk has often macrolide concentrations severalfold greater than in plasma (7). 

Analysis of Quantic Pharmacokinetic Study Robust Estimation of Tissue-to-Plasma Ratio... 

Tissue-to-plasma ratio is commonly determined from the ratio of average concentrations at specified time points. It is not uncommon, in practice, for the ratios to be calculated at selected time points corresponding to peak and trough concentrations, and the variations in the ratios are usually very large. This finding could be attributed in part to the variations in the concentrations and a lack of accounting for the correlation in observations from the biological matrices sampled from each subject. 

A toxicokinetic study was performed to determine the tissue-to-plasma ratio of a drug in development. An oral dose of a drug in development was administered to 18 rats, and each animal was killed at one of six specihed time points 0.5,1, 2, 4, 6, and 8 hours. Therefore, each animal had only 1 pair of concentrations, 1 each from plasma and tissue, respectively. Table 42.1 shows the data set from the study used in our investigation. The effect of correlation structure in the data set is also of interest. Thus, we investigated the effect of maintaining or breaking the relationship between tissue and plasma concentrations within the same animal, using both paired and unpaired tissue and plasma data to evaluate the effect on the robustness of estimation of tissue-to-plasma ratio. 

Thus, tissue-to-plasma ratio is estimated independently for each time point using the averaged concentration at each time point. Alternatively, the noncompart-mental AUC, actually the composite AUC, can be estimated using the trapezoidal rule. From this point, the use of the term naive data averaging approach will be reserved for estimation of AUC. The term unpaired independent time points approach will be reserved for use in cases where tissue-to-plasma ratio is calculated at each time point using a measure of central tendency (mean or median) of the measured concentrations without regard to the correlation structure in the observations. The term paired independent time points approach will be used when the pairing of observations is taken into account in the calculation of the tissue-to-plasma concentration ratio at each time point. 

TABLE 42.2 Tissue-to-Plasma Ratios Calculated Using the Unpaired Independent Time Points Approach"... 

TABLE 42.4 Tissue-to-Plasma Ratios Calculated from AUC ... 

Given the limitations associated with the naive data averaging approaches in estimating the tissue-to-plasma ratio, the RS approach is compared with the PpbB approach in subsequent sections. However, occasional references are made to the naive data averaging and independent time points approaches because of their use in common practice. 

OVERALL ASSESSMENT OF TISSUE-TO-PLASMA RATIO ESTIMATION 1047 (A) 10% (B)20%... 

OVERALL ASSESSMENT OF TISSUE-TO-PLASMA RATIO ESTIMATION... 

A nonparametric random sampling approach proposed by Chu and Ette (13) for the estimation of robust TPAR was compared with the PpbB and naive averaging approaches. Also, the estimation of tissue-to-plasma ratio using the independent time points approach was examined. It is obvious from Tables 42.2 and 42.3 that estimating tissue-to-plasma ratio independently at various times is a very... 

H.-M. Chu and E. I. Ette, A random samphng approach for robust estimation of tissue to plasma ratio from extremely sparse data. AAPS J 7(1) E249-E258 (2005). 

Schurr et al.43 reported the amino acid concentrations in various tissues of the rat. Using these data to calculate tissue-to-plasma ratios, it becomes apparent that the relative availability of plasma tryptophan to tissues is much less than that of other amino acids. The finding, described elsewhere, that tryptophan in serum or plasma can be present as free and bound (to plasma albumin) is unique among amino acids,44 and this further limits or controls the availability of tryptophan from the blood to organs or tissues, especially the brain. Tryptophan differs from other amino acids in that its concentration in plasma of rats increases (30 to 40%) after fasting, after insulin administration, or after consuming a carbohydrate meal.45... 

One of the highest concentrations was found in the lungs (tissue to plasma ratio >35 1) [108]. Lung concentrations of the parent compound measured by HPLC were >25-fold higher than plasma concentrations [107]. The distribution into lungs is clinically relevant since it is the primary site of antibacterial action of this drug. The disappearance of radioactivity from tissues was relatively rapid with most cleared 24 hr after a single oral dose [108]. 

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